Nutritional and genetic factors that alter methionine cycle metabolism in the central nervous system are associated with neurodegenerative processes as seen in Alzheimer's disease (AD). Deficiency of folate, which is more common in the geriatric population, has been clinically associated with AD. Inadequate cellular folate causes increases in the neurotoxic aminoacid homocysteine which mediates toxicity in part by increasing cellular oxidative stress and lipid peroxidation. A major genetic risk factor for AD and several other neurodegenerative disorders (AD) involves inheritance of a particular allele of apolipoprotein E, the epsilon4 allele (ApoE4). The presence of specific isoforms have been shown to modify the risk for several chronic neurological diseases and the ApoE4 allele is found in 40-65% of both sporadic and familial AD. New gene-targeted mouse models containing alleles that express specific human ApoE isoforms (E2, E3 and E4) are now commercially available. Early studies indicate that these human ApoE4 mice experience increased neurodegenerative events, such as increased oxidative damage, paralleling observations in man. The development of this model will allow for carefully designed studies to investigate mechanisms in which the increased neurodegenerative events associated with the presence of ApoE4 allele, are exacerbated or attenuated by the presence of specific environmental factors. The combined effects of increase oxidative stress from folate deficiency and the presence of the ApoE4 allele has not been studied and we hypothesize that greater oxidative stress will be observed in mice expressing with the ApoE4 isoform. We further hypothesize, as we have seen with the ApoE (-/-) mouse model, that the use of the specific agents that reduce cellular homocysteine formation, increase the synthesis of an important intracellular antioxidant (glutathione) and normalize cellular methylation status will reduce oxidative damage in brain tissue of folate deficient ApoE4 mice. These findings would be important since alternate therapies to folate supplementation in folate-compromised individuals which normalize homocysteine levels and oxidative status in the brain would be especially useful in the subset of the geriatric population possessing the ApoE4 allele since folate levels in geriatrics can be compromised by reduced intestinal absorption from multiple factors including multi-pharma drug-drug interactions.